scholarly journals SOD1 activity threshold and TOR signalling modulate VAP(P58S) aggregation via reactive oxygen species-induced proteasomal degradation in a Drosophila model of amyotrophic lateral sclerosis

2019 ◽  
Vol 12 (2) ◽  
pp. dmm033803 ◽  
Author(s):  
Kriti Chaplot ◽  
Lokesh Pimpale ◽  
Balaji Ramalingam ◽  
Senthilkumar Deivasigamani ◽  
Siddhesh S. Kamat ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Amyotrophic Lateral Sclerosis ◽  
Reactive Oxygen ◽  
Proteasomal Degradation ◽  
Oxygen Species ◽  
Drosophila Model ◽  
Lateral Sclerosis

scholarly journals Glutathione S-Transferase Rescues Motor Neuronal Toxicity in Fly Model of Amyotrophic Lateral Sclerosis

Antioxidants ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 615
Author(s):  
Sun Joo Cha ◽  
Yeo Jeong Han ◽  
Hyun-Jun Choi ◽  
Hyung-Jun Kim ◽  
Kiyoung Kim
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Neuromuscular Junctions ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Oxygen Species ◽  
Glutathione S Transferase ◽  
Neuronal Toxicity ◽  
Drosophila Model ◽  
Locomotive Activity ◽  
Underlying Mechanisms ◽  
Lateral Sclerosis

Transactive response DNA-binding protein-43 (TDP-43) is involved in the pathology of familial and sporadic amyotrophic lateral sclerosis (ALS). TDP-43-mediated ALS models in mice, Drosophila melanogaster, and zebrafish exhibit dysfunction of locomotor function, defective neuromuscular junctions, and motor neuron defects. There is currently no effective cure for ALS, and the underlying mechanisms of TDP-43 in ALS remain poorly understood. In this study, a genetic screen was performed to identify modifiers of human TDP-43 (hTDP-43) in a Drosophila model, and glutathione S-transferase omega 2 (GstO2) was found to be involved in hTDP-43 neurotoxicity. GstO2 overexpressed on recovered defective phenotypes resulting from hTDP-43, including defective neuromuscular junction (NMJ) boutons, degenerated motor neuronal axons, and reduced larvae and adult fly locomotive activity, without modulating the levels of hTDP-43 protein expression. GstO2 modulated neurotoxicity by regulating reactive oxygen species (ROS) produced by hTDP-43 in the Drosophila model of ALS. Our results demonstrated that GstO2 was a key regulator in hTDP-43-related ALS pathogenesis and indicated its potential as a therapeutic target for ALS.

scholarly journals Respiration enhances TDP-43 toxicity, but TDP-43 retains some toxicity in the absence of respiration

2018 ◽  
Author(s):  
Sei-Kyoung Park ◽  
Sangeun Park ◽  
Susan W Liebman
Keyword(s):  
Reactive Oxygen Species ◽  
Genetic Risk ◽  
Disease Model ◽  
Reactive Oxygen ◽  
Dna Binding Protein ◽  
Oxygen Species ◽  
Genetic Modifiers ◽  
Wild Type ◽  
Conserved Genes ◽  
Lateral Sclerosis

The trans-activating response DNA-binding protein 43 (TDP-43) is a transcriptional repressor and splicing factor. TDP-43 is normally mostly in the nucleus, although it shuttles to the cytoplasm. Mutations in TDP-43 are one cause of familial amyotrophic lateral sclerosis (ALS). In neurons of these patients, TDP-43 forms cytoplasmic aggregates. In addition, wild-type TDP-43 is also frequently found in neuronal cytoplasmic aggregates in patients with neurodegenerative diseases not caused by TDP-43 mutations. TDP-43 expressed in yeast causes toxicity and forms cytoplasmic aggregates. This disease model has been validated because genetic modifiers of TDP-43 toxicity in yeast have led to the discovery that their conserved genes in humans are ALS genetic risk factors. While how TDP-43 is associated with toxicity is unknown, several studies find that TDP-43 alters mitochondrial function. We now report that TDP-43 is much more toxic when yeast are respiring than when grown on a carbon source where respiration is inhibited. However, respiration is not the unique target of TDP-43 toxicity because we found that TDP-43 retains some toxicity even in the absence of respiration. We found that H2O2 increases the toxicity of TDP-43, suggesting that the reactive oxygen species associated with respiration could likewise enhance the toxicity of TDP-43. In this case, the TDP-43 toxicity targets in the presence or absence of respiration could be identical, with the reactive oxygen species produced by respiration activating TDP-43 to become more toxic or making TDP-43 targets more vulnerable.

Mitochondria as a source of reactive oxygen species

2009 ◽  
pp. c3 ◽  
Author(s):  
Helena M. Cochemé ◽  
Michael P. Murphy
Keyword(s):  
Reactive Oxygen Species ◽  
Reactive Oxygen ◽  
Oxygen Species
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